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Enhancement of proteasome activity by a small-molecule inhibitor of USP14

Author

Listed:
  • Byung-Hoon Lee

    (Harvard Medical School)

  • Min Jae Lee

    (Harvard Medical School)

  • Soyeon Park

    (Harvard Medical School)

  • Dong-Chan Oh

    (Harvard Medical School
    Natural Products Research Institute, College of Pharmacy, Seoul National University, San 56-1, Sillim, Seoul 151-742, Republic of Korea)

  • Suzanne Elsasser

    (Harvard Medical School)

  • Ping-Chung Chen

    (Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama at Birmingham)

  • Carlos Gartner

    (Harvard Medical School
    Present addresses: Department of Biological Sciences, 193 Galvin Life Sciences Center, Notre Dame, Indiana 46556, USA (C.G.); Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA (J.H.).)

  • Nevena Dimova

    (Harvard Medical School)

  • John Hanna

    (Harvard Medical School
    Present addresses: Department of Biological Sciences, 193 Galvin Life Sciences Center, Notre Dame, Indiana 46556, USA (C.G.); Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA (J.H.).)

  • Steven P. Gygi

    (Harvard Medical School)

  • Scott M. Wilson

    (Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama at Birmingham)

  • Randall W. King

    (Harvard Medical School)

  • Daniel Finley

    (Harvard Medical School)

Abstract

Proteasomes, the primary mediators of ubiquitin–protein conjugate degradation, are regulated through complex and poorly understood mechanisms. Here we show that USP14, a proteasome-associated deubiquitinating enzyme, can inhibit the degradation of ubiquitin–protein conjugates both in vitro and in cells. A catalytically inactive variant of USP14 has reduced inhibitory activity, indicating that inhibition is mediated by trimming of the ubiquitin chain on the substrate. A high-throughput screen identified a selective small-molecule inhibitor of the deubiquitinating activity of human USP14. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress.

Suggested Citation

  • Byung-Hoon Lee & Min Jae Lee & Soyeon Park & Dong-Chan Oh & Suzanne Elsasser & Ping-Chung Chen & Carlos Gartner & Nevena Dimova & John Hanna & Steven P. Gygi & Scott M. Wilson & Randall W. King & Dani, 2010. "Enhancement of proteasome activity by a small-molecule inhibitor of USP14," Nature, Nature, vol. 467(7312), pages 179-184, September.
    • Handle: RePEc:nat:nature:v:467:y:2010:i:7312:d:10.1038_nature09299
    DOI: 10.1038/nature09299
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    Cited by:

    1. Ka Ying Sharon Hung & Sven Klumpe & Markus R. Eisele & Suzanne Elsasser & Geng Tian & Shuangwu Sun & Jamie A. Moroco & Tat Cheung Cheng & Tapan Joshi & Timo Seibel & Duco Dalen & Xin-Hua Feng & Ying L, 2022. "Allosteric control of Ubp6 and the proteasome via a bidirectional switch," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Dongni Shi & Xianqiu Wu & Yunting Jian & Junye Wang & Chengmei Huang & Shuang Mo & Yue Li & Fengtian Li & Chao Zhang & Dongsheng Zhang & Huizhong Zhang & Huilin Huang & Xin Chen & Y. Alan Wang & Chuyo, 2022. "USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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